Cell fate regulation governed by a repurposed bacterial histidine kinase.
Cell fate regulation governed by a repurposed bacterial histidine kinase.
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DOI：
10.1371/journal.pbio.1001979
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发表时间：
2014-10
期刊：
影响因子：
9.8
通讯作者：
Shapiro L
中科院分区：
文献类型：
--
作者：
Childers WS;Xu Q;Mann TH;Mathews II;Blair JA;Deacon AM;Shapiro L
在柄杆菌属中调节不对称细胞分裂的途径涉及信号传导激酶，其催化输出结构域已被重新用作响应调节剂磷酸化状态的输入传感器-信息流的常规方向的逆转;这允许将简单的线性信号传导途径连接到复杂的真核生物样网络中。最简单的不对称分裂生物之一是新月柄杆菌。位于一个细胞极的DivL假组氨酸激酶通过与反应调节因子（RR）DivK相互作用控制全局转录因子CtrA的激活来调节细胞命运。DivL独特地在组氨酸磷酸化位点含有酪氨酸，并且可以在体内实现这些调节功能而没有激酶活性。DivL晶体结构的测定和野生型和位点特异性DivL突变体的生化分析表明，DivL PAS结构域调节DivK与DivK的结合特异性，这是由相邻结构域之间的变构分子内相互作用调节的。我们发现，DivL的催化结构域已被重新用作磷酸特异性RR输入传感器，从而逆转了在常规组氨酸激酶（HK）-RR系统中观察到的信息流，并耦合了一个复杂的信号蛋白网络用于细胞命运调控。在所有生命王国中，细胞类型多样性的产生是细胞分裂点不对称的结果。新月柄杆菌不对称分裂产生具有不同形态和行为的子细胞。在真核生物中，子柄杆菌细胞中信号蛋白的不均匀分布触发了相同基因组的差异读出。已知两种蛋白质分子-蛋白激酶（DivL）和反应调节剂（DivK）-之间的关键相互作用仅发生在一个子细胞中，从而调节分化。然而，绘制所观察到的驱动不对称分裂的信号相互联系一直难以与传统的细菌信号模型相协调。在这里，我们确定DivL如何检测和处理这个DivK信号。虽然DivL具有组氨酸激酶的典型结构，其通常通过调节适当反应调节剂的磷酸化状态起作用，但DivL的基本功能不需要激酶活性，并且DivL不添加或去除DivK中的磷酸盐。相反，我们发现DivL已将其输出激酶结构域转换为输入传感器结构域，该结构域特异性地检测磷酸化DivK，并且我们确定了DivL的关键特征，这些特征是这种特异性的基础。这种新的感觉功能的重新分配逆转了传统的激酶到反应调节器的信号流，并在逻辑上将线性信号通路耦合到复杂的真核生物样网络中以调节细胞发育。
The pathway that regulates asymmetric cell division in Caulobacter involves a signaling kinase whose catalytic output domain has been repurposed as an input sensor of the phosphorylation state of the response regulator – a reversal of the conventional direction of information flow; this allows wiring of simple linear signaling pathways into complex eukaryote-like networks. One of the simplest organisms to divide asymmetrically is the bacterium Caulobacter crescentus. The DivL pseudo-histidine kinase, positioned at one cell pole, regulates cell-fate by controlling the activation of the global transcription factor CtrA via an interaction with the response regulator (RR) DivK. DivL uniquely contains a tyrosine at the histidine phosphorylation site, and can achieve these regulatory functions in vivo without kinase activity. Determination of the DivL crystal structure and biochemical analysis of wild-type and site-specific DivL mutants revealed that the DivL PAS domains regulate binding specificity for DivK∼P over DivK, which is modulated by an allosteric intramolecular interaction between adjacent domains. We discovered that DivL's catalytic domains have been repurposed as a phosphospecific RR input sensor, thereby reversing the flow of information observed in conventional histidine kinase (HK)-RR systems and coupling a complex network of signaling proteins for cell-fate regulation. Across all kingdoms of life the generation of cell-type diversity is the consequence of asymmetry at the point of cell division. The bacterium Caulobacter crescentus divides asymmetrically to produce daughter cells that have distinct morphology and behavior. As in eukaryotes, an unequal distribution of signaling proteins in daughter Caulobacter cells triggers the differential read-out of identical genomes. A critical interaction between two protein molecules – a protein kinase (DivL) and a response regulator (DivK) – is known to occur exclusively in one daughter cell and to thereby regulate differentiation. However, mapping the observed signaling interconnections that drive asymmetric division has been difficult to reconcile with traditional models of bacterial signaling. Here we determine how DivL detects and processes this DivK signal. Although DivL has an architecture that is typical of histidine kinases, which normally act by regulating the phosphorylation state of the appropriate response regulator, DivL's essential functions do not require kinase activity and DivL does not add or remove phosphate from DivK. Instead we find that DivL has converted its output kinase domain into an input sensor domain that specifically detects phosphorylated DivK, and we identify key features of DivL that underlie this specificity. This novel reassignment of sensory functions reverses the conventional kinase-to-response-regulator signaling flow and logically couples linear signaling pathways into complex eukaryote-like networks to regulate cell development.
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影响因子：
9.9
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.051609998
发表时间：
2001-03-27
影响因子：
11.1
作者：
Jacobs, C;Hung, D;Shapiro, L
通讯作者：
Shapiro, L
影响因子：
1.8
作者：
Guarnieri, Michael T.;Blagg, Brian S. J.;Zhao, Rui
通讯作者：
Zhao, Rui
影响因子：
5.7
作者：
Blair, Jimmy A.;Xu, Qingping;Shapiro, Lucy
通讯作者：
Shapiro, Lucy